Submissions for variant NM_004370.6(COL12A1):c.3901C>T (p.Arg1301Ter)

gnomAD frequency: 0.00001  dbSNP: rs1304140510

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV001194634	SCV001364295	likely pathogenic	Ullrich congenital muscular dystrophy 2	2020-04-02	criteria provided, single submitter	research	ACMG codes: PVS1, PM2
Labcorp Genetics (formerly Invitae), Labcorp	RCV002559231	SCV003229390	pathogenic	Ullrich congenital muscular dystrophy 2; Bethlem myopathy 2	2024-04-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1301*) in the COL12A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL12A1 are known to be pathogenic (PMID: 24334604, 28973083). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with COL12A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 929448). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001194634	SCV005399873	likely pathogenic	Ullrich congenital muscular dystrophy 2	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene for glycine substitutions and is associated with myopathic Ehlers-Danlos syndrome (EDS) (PMID: 24334769). Loss of function is suspected to be the mechanism of disease for autosomal recessive Ullrich congenital muscular dystrophy 2 (MIM#616470). Many other LoF-type variants have been classified as pathogenic or likely pathogenic by clinical laboratories in ClinVar; however, current evidence for LoF-type variants causing dominant disease is limited (PMID: 31273343). (I) 0107 - This gene is associated with autosomal dominant disease. There are limited reports of autosomal recessive disease in the literature (PMIDs: 24334604, 28973083). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 3 heterozygotes, 0 homozygotes). (SP) 0703 - Other NMD-predicted variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. An NMD-predicted variant was observed as compound heterozygous with a splice variant in one affected individual, and a canonical splice variant with functional studies demonstrating exon 50 skipping causing a frameshift with an NMD-predicted outcome has been observed as homozygous in two siblings with an Ullrich-like myopathy (PMIDs: 24334604, 28973083). A heterozygous NMD-predicted variant has been reported in a child with hypotonia; however, it was not regarded as the diagnosis (PMID: 30907627). Within the VCGS cohort, a homozygous canonical splice variant predicted to result in NMD was also observed in an individual with severe neonatal presentation of arthrogryposis and muscular hypotonia. In addition, two heterozygous NMD-predicted variants have been observed, one in an individual with an Ullrich-like myopathy which segregated in their mother who had hypotonia and hypermobility, and one in an individual with a connective tissue disorder and delayed motor development. (SP) 0807 - This variant has no previous evidence of pathogenicity. It has been reported as pathogenic and heterozygous in an individual with muscular dystrophy with proximal weakness and a non-irritative myopathy in whom a second COL12A1 variant was not identified; however, a likely diagnosis was identified in an alternative gene (ClinVar, personal communication). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by duo analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign