Submissions for variant NM_001303256.3(MORC2):c.2044G>A (p.Val682Ile)

gnomAD frequency: 0.00061  dbSNP: rs144493873

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000558469	SCV000655811	likely benign	Charcot-Marie-Tooth disease axonal type 2Z	2024-11-18	criteria provided, single submitter	clinical testing
GeneDx	RCV001354178	SCV001757686	benign	not provided	2019-11-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000558469	SCV002554238	benign	Charcot-Marie-Tooth disease axonal type 2Z	2022-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002270667	SCV002554349	benign	Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002420523	SCV002721748	likely benign	Inborn genetic diseases	2020-08-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354178	SCV001548725	likely benign	not provided		no assertion criteria provided	clinical testing	The MORC2 p.Val682Ile variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs144493873) and ClinVar (classifed as likely benign by Invitae for Charcot-Marie-Tooth disease axonal type 2z). The variant was identified in control databases in 55 of 282628 chromosomes at a frequency of 0.0001946 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 47 of 24942 chromosomes (freq: 0.001884), Other in 2 of 7220 chromosomes (freq: 0.000277), South Asian in 3 of 30616 chromosomes (freq: 0.000098), Latino in 1 of 35434 chromosomes (freq: 0.000028) and European (non-Finnish) in 2 of 128980 chromosomes (freq: 0.000016), but was not observed in the Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.Val682 residue is not conserved in mammals and computational analyses (SIFT, AlignGVGD, BLOSUM, PolyPhen-2, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.