Submissions for variant NM_080680.3(COL11A2):c.966dup (p.Thr323fs)

dbSNP: rs748440351

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000592394	SCV000702400	pathogenic	not provided	2016-10-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778790	SCV000915161	uncertain significance	COL11A2-Related Disorders	2018-01-30	criteria provided, single submitter	clinical testing	The COL11A2 c.966dupC (p.Thr323HisfsTer19) variant results in a frameshift and is predicted to result in premature termination of the protein. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for COL11A2-related disorders.
GeneDx	RCV000592394	SCV001167938	pathogenic	not provided	2023-01-17	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29456477, 26445815, 31299979, 31980526, 34265623, 31850270, 33597575, 36056583)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001195605	SCV001366004	uncertain significance	not specified	2019-08-14	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Thr323HisfsX19 variant in COL11A2 has been previously reported in 3 Iranian individuals with hearing loss who were homozygous for the variant. It should be noted that consanguinity was reported for 1 individual, and was likely present for the remaining 2 (Sloan-Heggen 2015, Vona 2017). It has been reported in ClinVar (Variation ID 497724). This variant has also been reported in 34/281618 of the total chromosomes by gnomAD, with the highest frequency of 0.019% (7/35422) in Latino chromosomes (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 323 and leads to a premature termination codon 19 amino acids downstream. However, this variant is present in an in-frame exon that is only present in 1 transcript of COL11A2. Therefore, the impact to the protein is uncertain. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied: PVS1_Moderate, PM2_Supporting, PM3_Supporting.
Center for Reproductive Medicine, Peking University Third Hospital	RCV001257368	SCV001433894	likely pathogenic	Heart, malformation of; Thickened nuchal skin fold; Cystic hygroma; Short long bone	2019-10-16	criteria provided, single submitter	clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814194	SCV001755264	pathogenic	Ear malformation	2021-07-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000592394	SCV002023276	likely pathogenic	not provided	2020-09-25	criteria provided, single submitter	clinical testing
Invitae	RCV000592394	SCV002233340	pathogenic	not provided	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr323Hisfs*19) in the COL11A2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL11A2 are known to be pathogenic (PMID: 10677296, 21204229). This variant is present in population databases (rs748440351, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive COL11A2-related conditions (PMID: 29456477, 31299979). ClinVar contains an entry for this variant (Variation ID: 497724). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
3billion	RCV002250665	SCV002521707	pathogenic	Autosomal recessive nonsyndromic hearing loss 53	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.012%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 33111345). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID:33111345). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000497724). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genetics Laboratory, Department of Biology, Semnan University	RCV002250665	SCV002569140	pathogenic	Autosomal recessive nonsyndromic hearing loss 53	2019-01-15	criteria provided, single submitter	case-control	The identified mutation leads to frameshift in the coding part of RPGR gene. Hence, this substitution alters the amino acid sequence and leads to a premature stop codon at position 323 with the complete loss of rest of the protein sequence leading to truncated protein.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000592394	SCV001959051	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000592394	SCV001973397	pathogenic	not provided		no assertion criteria provided	clinical testing