Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_001100.4(ACTA1):c.990+1G>T

CA1442746

464139 (ClinVar)

Gene: ACTA1
Condition: alpha-actinopathy
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 7b8b8c9c-da02-4129-b0b8-42009c27d9cc
Approved on: 2024-08-07
Published on: 2024-12-19

HGVS expressions

NM_001100.4:c.990+1G>T
NM_001100.4(ACTA1):c.990+1G>T
NC_000001.11:g.229431720C>A
CM000663.2:g.229431720C>A
NC_000001.10:g.229567467C>A
CM000663.1:g.229567467C>A
NC_000001.9:g.227634090C>A
NG_006672.1:g.7377G>T
ENST00000366683.4:c.990+1G>T
ENST00000684723.1:c.855+1G>T
ENST00000366683.3:c.621+1G>T
ENST00000366684.7:c.990+1G>T
NM_001100.3:c.990+1G>T
More

Pathogenic

Met criteria codes 2
PVS1_Strong PM3_Strong
Not Met criteria codes 18
BS4 BS3 BS1 BP7 BP3 BP4 BP1 BP2 PM2 PM5 PM1 PM4 PS1 PS3 BA1 PP1 PP3 PP2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ACTA1 Version 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Congenital Myopathies VCEP
The variant c.990+1G>T in ACTA1 occurs within the canonical splice donor site (+1) of intron 6. It is predicted to cause skipping of biologically-relevant-exon resulting in an out of frame deletion. However, it is predicted to escape nonsense mediated decay and remove >10% of the protein (PVS1_Strong). The highest minor allele frequency in gnomAD v4.1.0 is 0.00001883 (31/1180028 alleles) in the European (non-Finnish) population (no population codes met). This variant has been reported in trans with a pathogenic variant in two probands with nemaline myopathy (PMID:19562689, LOVD (https://www.dmd.nl/)), and homozygous in one proband with nemaline myopathy (https://helda.helsinki.fi/handle/10138/157180) which meets PM3_Strong. In summary, the variant meets the criteria to be classified as pathogenic for autosomal recessive alpha-actinopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PVS1_Strong, PM3_Strong (ClinGen Congenital Myopathies VCEP specifications version 1; 08/07/2024).
Met criteria codes
PVS1_Strong
This variant occurs within the canonical splice donor site (+1) of the last intron (intron 6). It is predicted to cause skipping of biologically-relevant-exon 6/7, resulting in an out of frame deletion. However, it is predicted to escape nonsense mediated decay and remove >10% of the protein (PVS1_Strong)
PM3_Strong
One proband with this variant in trans with a pathogenic variant (Ala146Profs*46) was found in LOVD. Two publications report this variant as in trans with a pathogenic variant (Tyr190*) in one proband (PMID:19562689) and homozygous in another proband (http://urn.fi/URN:ISBN:978-951-51-1622-2) which meets the criteria for PM3_Strong
Not Met criteria codes
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
The highest minor allele frequency in gnomAD v4.1.0 is 0.00001883 (31/1180028 alleles) in the European (non-Finnish) population (no population codes met).
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
The highest minor allele frequency in gnomAD v4.1.0 is 0.00001883 (31/1180028 alleles) in the European (non-Finnish) population (no population codes met).
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
The highest minor allele frequency in gnomAD v.2.1.1 is 0.00001760 (2/113660 alleles) in the European (non-Finnish) population which does not meet the criteria for PM2_P, BA1 or BS1
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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